The present invention provides peptides for suppressing autoimmune arthritis that do not provoke a material immunogenic response from T cells.
Autoimmune arthritis afflicts a large number of people and takes many forms including, rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, spondylo arthritis, relapsing polychondritis and other connective tissue diseases. These arthritic conditions occur in mammals when T cells are activated by particular antigens or complexes containing antigens. When such activation occurs, proteolytic enzymes are produced which degrade tissues of the person or mammal afflicted by arthritis. The tissue targets of autoimmune arthritis are constituents of connective tissues in joints and tendons of mammals and ordinarily include type II collagen. Indeed autoimmune arthritis can be induced in mice, humans and other mammal by immunizing them with type collagen II derived from cartilage of the same or different mammals. See, Andriopoulos N A, Mestecky J. Miller E J, Bradley E L: Antibodies to native and denatured collagen in sera of patients with rheumatoid arthritis. Arth. Rheum. 19:613-617, 1976; Wooley P H, Luthra S. Singh S. Huse A, Stuart J M, David C S: Passive transfer of arthritis in mice by human anti-type II collagen antibody. Mayo Clinic Proc. 59:737-743, 1984.
Autoimmune arthritis in mammals develops when T cells are activated by immunogenic complexes referred to as trimolecular complexes. These complexes are formed between antigenic peptides and major histocompatibility complex molecules (MHC). Buus, S., A. Sette, and H. M. Grey, (1987) xe2x80x9cThe interaction between protein-derived immunogenic peptides and Iaxe2x80x9d. Immuno. Rev. 98:115. These complexes then are recognized by the T cell receptors of antigen-specific T cells to form the tri-molecular complexes which result in the activation and subsequent functioning of T cells and in the development of arthritis.
Native type II collagen (CII) can induce arthritis in susceptible individuals. Certain fragments of native CII also induce an immunogenic response. Some of those immunogenic fragments and some of their analogs may also suppress the disease. Frequently this suppression occurs because T cell tolerance is developed. That is, the T cells are disabled from responding to the antigen or trimolecular complex containing the antigen. This immunogenic response (T cell tolerance) limits the therapeutic potential for the native polypeptide fragments and many of their analogs because the body develops immunity to the fragment after its first use. Subsequent treatments with the native fragments of CII are therefore expected to be ineffective. It would therefore be desirable to develop peptides that suppress autoimmune arthritis without inducing a material immunogenic response or, more preferably, without inducing any immunogenic response at all.
Peptides have been identified which may be capable of inhibiting specific T cell responses by blocking formation of the trimolecular complex in some way rather than by disabling the T cells. Babbitt, B. P., G. Matsueda, E. Haber, E. R. Unanue, and P. M. Allen, 1986, Antigenic Competition at the Level of Peptide-Ia Binding. Proc. Natl. Acad. Sci. USA 83:4509; Adorini, L. and Z. A. Nagy, 1990, Peptide Competition for Antigen Presentation. Immuno. Today. 11:21. Peptides have been used to suppress or prevent murine experimental autoimmune encephalomyelitis (EAE). Wraith, D. C., D. E. Smilek, D. J. Mitchell, L. Steinman, and H. O. McDevitt, 1989, Antigen Recognition in Autoimmune Encephalomyelitis and the Potential for Peptide-Mediated Immunotherapy. Cell 59:247; Lamont, A. G., A. Sette, R. Fujinami, S. M. Colon, C. Miles, and H. M. Grey, 1990, Inhibition of Experimental Autoimmune Encephalomyelitis Induction in SJL/J Mice By Using a Peptide with High Affinity for I-As Molecules. J. Immunol. 145:1687; Salao. K., S. S. Zamvil, D. J. Mitchell, S. Hodgkinson, J. B. Rothbard, and L. Steinman, 1989, Prevention of Experimental Encephalomyelitis with Peptides that Block Interaction of T Cells with Major Histocompatibility Complex Protein. Proc. Natl. Acad. Sci. USA. 86:9470. Investigators, using the EAE animal model, have demonstrated inhibition of the induction of experimental encephalomyelitis with synthetic peptides. When mice bearing the H-2u haplotype were co-immunized with an analog peptide and an encephalogenic peptide (amino acid residues 1-9 of myelin basic protein), disease did not develop. An unrelated peptide, known to bind to I-AS, was used to inhibit the development of encephalomyelitis by the EAE-inducing antigen. Lamont, A. G., A. Sette, R. Fujinami, S. M. Colon, C. Miles, and H. M. Grey, 1990, Inhibition of Experimental Autoimmune Encephalomyelitis Induction in SJL/J Mice by Using a Peptide with High Affinity for I-As molecules. J. Immunol. 145:1687. The ability of some peptides to xe2x80x9ccompetexe2x80x9d for binding to class II MHC molecules in vitro has been demonstrated. Werdelin, O, 1982, Chemically Related Antigens Compete for Presentation by Accessory Cells to T Cells. J. Immunol. 129:1883; Rock, K. L. and B. Benacerraf, 1984, Selective Modification of a Private I-A Allostimulating Determinant(s) Upon Association of Antigen With An Antigen-Presenting Cell. J. Exp. Med. 159:1238; Babbitt, B. P., G. Matsueda, E. Haber, E. R. Unanue, and P. M. Allen, 1986, Antigenic Competition at the Level of Peptide-Ia Binding. Proc. Natl. Acad. Sci. USA 83:4509.
The goal of providing peptides that block formation of trimolecular complexes without inducing material antigenic responses, however, is not always obtainable nor is success in obtaining that goal easily predictable. The strategy of developing a synthetic analog peptide having such a combination of features is not known to be a consistently reliable technique for developing therapeutically useful peptides in all autoimmune diseases or for autoimmune arthritis specifically. Two parameters that affect the ability of synthetic peptides to compete for antigen presentation are: 1) the relative affinity of antigenic and competitor peptides for the MHC molecule, and 2) the avidity of T cells for the activating ligand. One can not be reasonably assured of being able to develop a peptide which will have the required affinity and avidity for MHC yet that does not illicit a material immunogenic response from T cells.
In addition, use of analog peptides may make autoimmune arthritis worse rather than suppressing it in some instances. This problem occurs primarily when the analog stimulates T cell immunity. The resulting tolerance can subsequently break down. The disease then worsens and administration of the analog can not suppress it. This problem is particularly a concern with analogs of CII because the native CII fragments are known to be quite immunogenic and their analogs tend to also have a high level of immunogenicity. This makes more difficult and unlikely the development of analog peptides that suppress autoimmune arthritis without prompting an undesirable immunogenic T cell response.
The present invention provides analog peptides of fragments of CII protein, which contain a T cell antigen, which analog peptides suppress autoimmune arthritis. The analogs disrupt formation of trimolecular complexes of autoimmune antigenic peptide, MHC and T-cell receptor but do not provoke a material immunogenic response.
The present invention includes analogues of CII 245-270 and, more specifically, analogs of CII 260-270 peptide and of CII 245-270 [s 260, 261, 2631] peptide.
Moreover, the present invention provides the following peptides
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